A systematic review of health effects of electronic cigarettes

An up-dated systematic review of health effects of electronic cigarettes Charlotta Pisinger PhD, MPH, Ass Prof The Capital Region of Denmark

Conflict of interest • I have nothing to declare



149 studies identified

General findings • Many methodological challenges – No ‘standard e-cigarette’ – No ‘standard vaping-machine’ – Often very few brands tested • Findings only apply to the specific brand and batch – Studies of adverse events: selection bias – Human experiments: e-cig naïve volunteers, very short term exposure – Animal experiments: too intensive exposure? – Overheating?.....

General findings • Misleading/missing information on product ingredients • Most studies compare with cigarettes/smoking – But an e-cig is a completely different product • No long-term effect studies • >1/3 of studies: conflict of interest – 26% of studies were performed by tobacco industry

Characteristics of studies sponsored by tobacco industry • Never find negative health effects • No/little discussion of weaknesses of study • Examples: – High values in some samples are ignored or presented as not- significant means of all samples – Do not use cell systems that are most sensitive to e-cig vapor

Studies on fluid/vapor Harmful substances • Fine/ultrafine particles Very conflicting • Carcinogenic tobacco specific results: nitrosamines – Most/few/no brands • Carcinogenic carbonyls – Most/few/no samples • Harmful metals – High concentrations • Volatile organic compounds /low or trace levels • Polycyclic aromatic hydrocarbons

Example of conflicting results: particles • Particle size • E-cigs and conventional cigs produce aerosols with comparable particle sizes Fuoco FC 2014, Ingebrethsen BJ 2012, Zhang Y 2013 • Particles from e-cigs are much smaller Laugesen M 2019 than in tobacco smoke • Particles from e-cigs are much bigger Bertholon JF 2013 than in tobacco smoke • Vapor size distribution alters in the human lung and leads to exhalation of smaller particles Schripp T 2013 • Particle count • Extremely high particle doses deposited in a human lung model FDA 2014, Bates MN 2007 • Double of the dose from tobacco smoke Bates MN 2007 • The same dose as in tobacco smoke Fuoco FC 2014, Ingebrethsen BJ 2012 • Concentration to be lower, up to an order of magnitudes lower, than in smoke Czogala J 2014, McAuley TR 2012, Pellegrino RM 2012 • Conventional cigs produce more particles initially, but particle counts converge to a level comparable to the condensed vapor Zhang Y 2013

Toxicity assessments 2015 – 42 samples/15 brands 2013 – 20 fluids/10 brands • None of the products were • Half of the liquids analyzed totally exempt of potentially contained up to five times the toxic compounds and a maximum amount of minority of liquids, especially impurities specified in the those with flavorings, showed European Pharmacopoeia particularly high ranges of standards Etter JF 2013 chemicals, causing concerns about their potential toxicity in case of chronic oral exposure Varlet V 2015

Experiments: cells exposed to fluid/vapor/vapor extract • Dysregulation of gene expression/vapor can change gene expression in a similar way to tobacco smoke Park SJ et al. Clinical Cancer Research Conference, June 2014; Palpant NJ PLoS One 2015 • Profound adverse effects on the metabolomic state of human bronchial epithelial cells similar to those seen with tobacco smoke condensate Aug A European Respiratory Society Annual Congress 2014 • Dose-dependent loss of lung endothelial barrier function Schweitzer KS et al. Am J Physiol Lung Cell Mol Physiol. 2015 May 15

Experiments: cells exposed to fluid/vapor/vapor extract • Promotes Human rhinovirus infection Dinicola S et al. Toxicol In Vitro 2013; 27(8):2256-2263 • Platelet aggregation was enhanced; enhancement mirrored . the effects of tobacco smoke extracts. Platelets were more likely to participate in coagulation based reactions Chen L 2015 The FASEB Journal vol. 29 no. 1 Supplement 631.6 • Cytotoxic/toxicological effects • especially on embryonic and neonatal stem cells Scheffler S et al. Int J Environ Res Public Health. 2015 Apr 8;12(4):3915-25. Varlet V et al. Int J Environ Res Public Health. 2015 Apr 30;12(5):4796-815. Tierney AP et al. Tob Control. 2015 Apr 15. Farsalinos K. et al. Int J Environ Res Public Health. 2013, 10, 5146-5162 Bahl V et al. Reprod.Toxicol. 2012; 34:529-537 Willershausen I. Head & Face Medicine 2014, 10:39

Experiments: cells exposed to fluid/vapor/vapor extract Oxidative stress and inflammation Dinicola S 2013, Shivalingappa et al. April 201, Cervellati F 2014, Schweitzer KS 2015, Rubenstein D 2015 , Higham 2014, Lerner 2015, Schweitzer KS 2015, Scheffler S 2015 • Increased oxidative stress • Increased apoptosis • Redox imbalance • Increased release of cytokines and pro-inflammatory mediators • Increased inflammation • Effects similar to those caused by tobacco smoke Higham 2014, Lerner 2015, Schweitzer KS 2015 • Oxidative stress was approx. 5 times lower than in cells exposed to smoke Scheffler S 2015

Animal experimental studies • Rats – short term exposure caused hyper-and metaplasia in the larynx Salturk Z J Voice 2015. • Mice - longer term exposure (4 month) caused asthma and emphysema Geraghty 2014 • Mice – short term exposure Lim HB, Kim SH. Toxicol Res 2014; 30(1):13-18 , Sussan T et al. PLOS ONE | DOI:10.1371/journal.pone.0116861 February 4, 2015; Lerner CA et al. PloS one 10: e0116732, 2015 – Asthmatic reaction and inflammation of airways – Increased oxidative stress – Decreased pulmonary anti-bacterial defense – Higher mortality when exposed to virus infection

Animal experimental studies • Pericardial edema and a negative effect on heart function and heart development in zebrafish Palpant NJ et al. PLoS One. 2015 May 15;10(5):e0126259 • Neonatal mice – short term exposure McGrath-Morrow SA et al. PLoS One 2015; 10(2):e0118344 – adverse impact on weight gain – diminished alveolar cell proliferation – impairment in postnatal lung growth

Human experimental studies Pulmonary system Marini S et al. Toxicol Appl Pharmacol 2014; 278(1):9-15, Flouris et al. Inhal.Toxicol. 2013; 25:91-101, Vardavas et al. Chest 2012; 141:1400-1406, Ferrari M , BMC Plumonary Medicine2012; 15 • Effects that remind of those seen with smoking (healthy subject + asthmatics) – Increased airway resistance – Airway obstruction Cardiovascular system – No negative effect on elasticity and stiffness of ascending aorta Farsalinos K2013 – Do not impair the cerebral pressure-flow relationship Colbyl H 2015 – No influence on complete blood count or cardiac function Flouris AD et al. 2012 – Increased heart rate – Blood pressure? Methodological problems: small Battista Let al. Circulation Conf: Am Heart Association 2013 studies Czogala J et al. Przegl.Lek. 2012; 69:841-845 lnsufficient + short term Flouris AD et al. Food Chem.Toxicol. 2012…. exposure

Toxicants in urine • Potentially carcinogenic • Urinary toxicant and substance acrolein found in carcinogen metabolites were urine Schober et al. Int J Hyg Environ significantly lower in current e- Health 2014; 217(6):628-637 cig users than in conventional smokers but a few e-cig users had higher than expected levels of total NNAL (metabolites of the tobacco- specific nitrosamine and lung carcinogen); lower than in smokers but higher than when exposed to second hand smoking Hecht SS et al. Nicotine Tob Res 2015; 17(6):704-709.

Adverse events Surveys and longitudinal studies Conflicting results • Symptoms from all organ • No serious adverse events in prospective studies systems • No serious adverse events in • Often several organ systems RCT Bullen C et al. The Lancet 2013 Sep 9 • Decrease in respiratory symptoms and improvements in general health Selection bias

Adverse events Case reports • Contact dermatitis • Acute eosinophilic pneumonitis • Subacute bronchial toxicity • Exogenous lipid pneumonia • Reversible cerebral vasoconstriction syndrome • Atrial fibrillation • Lichen planus • Lingua villosa nigra • Colonic necrotizing enterocolitits in a new born child • Relapse of colitis ulcerosa symptoms Time association and reversibility • Remission in a colitis ulcerosa patient • Beneficial effects on idiopathic chronic neutrophilia

Unexpected effects? Interaction between radon and side-stream vapor • The increase in the attached Potential Alpha Energy Concentration was higher for e-cigs than for traditional cig • Aerosol from e-cigs operated as a carrier of the radon progeny and, as a consequence it decreased the “plate out” of the radon daughter Vargas Trassierra C et al. Atmospheric Environment 2014 doi: 10.1016/j.atmosenv.2014.06.017

Conclusion on health effects No strong conclusions can be drawn – Lack of long-term follow-up – Many studies: conflict of interest – Many methodological problems – Few, often small studies • Conflicting results • Many studies indicate harm • Especially experimental studies E-cigarettes can hardly be called safe - but are most probably less harmful than cigarettes

Current evidence interpreted in a public health perspective



Real-life: 8 out of 10 vapers also smoke Danish nationally representative sample. Survey. ”Rygevaneundersøgelse 2013. Udført af Gallup for Sundhedsstyrelsen, Kræftens Bekæmpelse, Hjerteforeningen og Danmarks Lungeforening” • 73.7 % Poland. Youth. Goniewicz M, Int J Public Health, Nov 2015 • 76.3% USA. Youth. CDC, MMWR, 62(35), Sept 6, 2013 • 76.8% Georgia. Youth. King BA et al. Nicotine and Tobacco Research, Sept 2014. • 76.5% Kansas US (2012-2013). Adults Christensen T, Prev Med Dec 2014 • 80.5% Korea. Youth. Lee S, J Adolesc Health 2014 • 77.7% Canada, nationally representative sample Reid JL, Prev Med Sept 2015

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Health effects of dual use ???????? • Worst case scenario: synergetic interaction • Like of asbestos and smoking

Dual use ..but if many/most quit –then dual use by few might be acceptable EC + EC to quit Quit Relapse smoking

Real-life: longitudinal population-based studies on smoking cessation Probability of being abstinent from smoking 1.2 for e-cig users  Quit rates HIGHER 1  0.8 0.6 for e-cig users Quit rates LOWER 0.4 0.2 0 No use of Adkison Vickerman Grana Choi 2014 Al-Delaimi Pearson Brose Borderud Sutfin Biener e-cig 2013 2013 2013 2015 2015 2015 2014# 2015# 2015* * Intensive users: > 6 times higher quit # presented as probability of smoking in article rates (min. 30 days smoke-free)

Undermines the wish to quit?

Harm reduction Harm reduction for smokers Harm reduction for public health



Never-smokers among young e-cigaret users % 35 30 25 20 Among ever EC users 15 Among current 10 EC users 5 0



Poland: explosive increase in vaping Increase from 17% to 62% Increase from 6% to 30% Ever smoked Ever used e-cig Current smoker Current e-cig user Current smoker + e-cig user Goniewicz ML, Rise in Electronic Cigarette Use Among Adolescents in Poland. J of Adolescent Health, 2014, 5 (5) Pages 713–715, November 2014

Poland: explosive increase in smoking Increase in smoking from 24% to 38% Increase in dual use from 4% to 22% Ever smoked Ever used e-cig Current smoker Current e-cig user Current smoker + e-cig user Goniewicz ML, Rise in Electronic Cigarette Use Among Adolescents in Poland. J of Adolescent Health, 2014, 5 (5) Pages 713–715, November 2014

 Renormalisation Social norm of smoking Dual use Uptake Toxicity/ Uptake by adverse events by ex- never- smokers smokers Under- Cessation mining Gateway to tool wish to smoking quit Tobacco industry

Who will have a health gain? Risk of re-normalisation of Health gain for reluctant smoking in society smokers who switch to EC Increased risk for smokers Health gain for smokers who switch to EC instead who substantially reduce of stopping smoking smoking by use of EC Increased risk for dual Substantial health gain for users (smoking + EC) smokers who quit by use of EC Increased risk for ex- smokers using EC Increased risk for never smokers using EC EC: Electronic cigarettes

Thank you for your attention